Effect of dietary supplementation with recombinant human lysozyme on growth performance, antioxidative characteristics and intestinal health in broiler chickens.

Lysozyme is often used as a feed additive to act as an antibacterial protein that boosts the immune system of livestock and poultry while protecting against pathogens. To investigate effects of recombinant human lysozyme (rhLYZ) rom Pichia pastoris and chlortetracycline on broiler chicken's production performance, antioxidant characteristics, and intestinal microbiota, a total of 200, one-day-old male Arbor Acres broiler chickens (46.53±0.42 g) were selected for a 42-day experiment. Dietary treatments included: a basal diet of corn-soybean meal supplemented with either 0 mg/kg (CON), 50 mg/kg aureomycin (ANT), 20 mg/kg rhLYZ (LOW), 60 mg/kg rhLYZ (MEDIUM), or 180 mg/kg rhLYZ (HIGH). Compared with CON, MEDIUM diet increased (p < 0.05) average daily gain (ADG)(= 67.40g) of broilers from day 22 to 42. In the early (= 1.29) and overall phases (= 1.69), MEDIUM led to a reduction (P<0.05) in feed conversion ratio (FCR) of broiler chickens. Furthermore, in comparison to the CON and ANT, MEDIUM exhibited reduced (P<0.05) levels of INF-γ and TNF-α in the serum. In the cecum, the abundance of Monoglobus and Family_XIII_AD3011_group was lower (P < 0.05) in the MEDIUM treatment compared to CON. Overall, supplementation of 60 mg/kg of rhLYZ improved growth performance, nutrient utilization efficiency, and serum immune function, while also influencing composition of intestinal microbiota. This suggests lysozyme's potential to replace antibiotic additives in feed.

Removal of leftover feed shapes environmental microbiota and limits houseflies-mediated dispersion of pathogenic bacteria in sow breeding farms.

BACKGROUND: Intensive swine breeding industry generates a complex environment where several microbial interactions occur and which constitutes a challenge for biosafety. Ad libitum feeding strategies and low levels of management contribute to residual and wasted feed for lactating sows, which provides a source of nutrients and microbial source for houseflies in warm climates. Due to the absence of the all-in/all-out system, the coexistence of sows of two production stages including gestating and lactating sows in the farrowing barn may have potential negative impacts. In this research, we evaluated the effects of lactating sow leftover on the environmental microbiota of the farrowing barn and the contribution of microbial environments to the gestating sow fecal bacterial structure with a 30-day-long treatment of timely removing lactating residual feed. RESULTS: Houseflies in the farrowing barn mediate the transmission of microorganisms from lactating sow leftover to multiple regions. Leuconostoc, Weissella, Lactobacillus and Pediococcus from the leftover which can produce exopolysaccharides, are more capable of environmental transmission than pathogenic microorganisms including Staphylococcus and Streptococcus and utilize houseflies to achieve spread in environmental regions of the farrowing barn. Leftover removal treatment blocked the microbial transmission chain mediated by houseflies, downregulated the relative abundance of pathogenic bacteria including Escherichia-Shigella and Streptococcus among houseflies, environmental regions and fecal bacteria of gestating sows in the farrowing barn and effectively attenuate the increment of Weissella and RF39 relative abundance in gestating sow feces due to the presence of lactating sows. CONCLUSIONS: Lactating sow leftover is a non-negligible microbial contributor of environment in farrowing barn whose transmission is mediated by houseflies. A 30-day-long treatment of removing lactating sow residual feed cause significant changes in the microbial structure of multiple environmental regions within the farrowing barn via altering the microbiota carried by houseflies. Meanwhile, lactating sow leftover affect the fecal microbial structure of gestating sows in the same farrowing barn, while removal of lactating sow leftover alleviates the contribution of microbial transmission.

Opinions over targets for blood pressure control after mechanical thrombectomy in patients with acute ischemic stroke: baseline survey for the ENCHANTED2/MT trial in China.

BACKGROUND: Although guidelines recommend a target blood pressure 185-180/105-110 mmHg after mechanical thrombectomy for acute ischemic stroke (AIS), there is limited randomized evidence to support this level. We surveyed candidate institutions about the approach to blood pressure management in this patient group in preparation for inviting them to participate in the Enhanced Blood Pressure Control after Endovascular Thrombectomy for the Acute Ischemic Stroke Trial (ENCHANTED2/MT). METHODS: Physicians from a professional network of institutions that met mechanical thrombectomy qualification requirements were invited to participate in an online questionnaire covering basic clinical information as well as questions on blood pressure management. RESULTS: We invited 88 sites to participate with 44 (50%) ultimately joining the trial, and a total of 88 physicians finished the survey. The median number of annual mechanical thrombectomy cases performed per site was 89 [IQR 65-150]. Only 38 (43%) institutions strictly adhere to guidelines when managing the blood pressure of mechanical thrombectomy patients. The most popular blood pressure target for reperfusion patients was 140-160 mmHg (n=47, 53%), and <120 mmHg (n=28, 32%). Fewer hospital stroke beds (40 [21-57] vs. 60 [39-110], p = 0.01) and lower proportion of elevated blood pressure after mechanical thrombectomy (25% [10%-50%] vs. 50% [20%-70%], p = 0.02) were related to a more aggressive blood pressure target (<120 mmHg). Urapidil (n=82, 93%) and calcium channel blockers (CCBs) (n = 87, 99%), were the most widely used antihypertensive drugs, respectively. CONCLUSIONS: According to the survey, unstandardized blood pressure management protocols are performed in mechanical thrombectomy patients at institutions across China, which is different from prior survey from another country. More high-quality studies are needed to guide clinical practice.

Intensive blood pressure lowering and renal function in ischemic stroke patients: secondary analysis of ENCHANTED trial.

BACKGROUND: Renal failure is a major safety concern of intensive systolic blood pressure (SBP) lowering. We aimed to determine the effect of this treatment on early change in renal function in participants of the international Enhanced Control of Hypertension and Thrombolysis Stroke Study (ENCHANTED). METHODS: Post-hoc analysis of the ENCHANTED BP-arm in which thrombolyzed patients with acute ischemic stroke (AIS) were randomized to intensive (target 130-140 mm Hg within 1 h) or guideline-recommended (target <180 mm Hg) management within 6 h of symptom onset. Primary outcome is early change in renal function, defined by a difference in estimated glomerular filtration rate (∆eGFR = 24 h - baseline eGFR), analyzed using linear regression with adjustment for clinical variables. Key SBP parameters were attained (mean), variability (standard deviation [SD]) and magnitude of reduction within 24 h. RESULTS: Of 2151 participants (mean age 66.9 years; 38% female) included with available baseline eGFR, there were significant differences in attained 144.3±10.2 vs 149.8±12.0 [5.5 mm Hg]; P<0.0001), variation (15.1±5.4 vs 14.0±5.6 mm Hg; P<0.0001) and magnitude of reduction (44.6±16.2 vs 38.7±17.6 mm Hg; P<0.0001) in SBP within 24 hours. 1718 (79.9%) participants with complete follow-up eGFR were included in the primary analysis, and there was no significant difference in ∆eGFR (adjusted mean difference -1.10, 95% confidence interval [CI] -3.14 to -0.94; P=0.29) between the intensive and guideline groups, respectively. The neutral effect on ∆eGFR was consistent in patients with different baseline eGFR stages and in sensitivity analysis after multiple imputation for missing follow-up eGFR. SBP variability was significantly associated with decreasing ∆eGFR (per 5 mm Hg increase by category: adjusted mean difference -1.35, 95%CI -2.43 to -0.28; P for trend=0.01). CONCLUSIONS: Intensive SBP lowering with a target of 130-140 mm Hg had no impact on early renal function in thrombolyzed AIS patients. Wide SBP variability was associated with a larger decline in eGFR. CLINICAL TRIAL REGISTRATION: ENCHANTED is registered at ClinicalTrials.gov (NCT01422616).

Mechanistic Evaluation of Diffusion Weighted Hyperintense Lesions After Large Spontaneous Intracerebral Hemorrhage: A Subgroup Analysis of MISTIE III.

BACKGROUND: Ischemic lesions on diffusion weighted imaging (DWI) are common after acute spontaneous intracerebral hemorrhage (ICH) but are poorly understood for large ICH volumes (> 30 mL). We hypothesized that large blood pressure drops and effect modification by cerebral small vessel disease markers on magnetic resonance imaging (MRI) are associated with DWI lesions. METHODS: This was an exploratory analysis of participants in the Minimally Invasive Surgery Plus Alteplase for Intracerebral Hemorrhage Evacuation phase 3 trial with protocolized brain MRI scans within 7 days from ICH. Multivariable logistic regression analysis was performed to assess biologically relevant factors associated with DWI lesions, and relationships between DWI lesions and favorable ICH outcomes (modified Rankin Scale 0-3). RESULTS: Of 499 enrolled patients, 300 had MRI at median 7.5 days (interquartile range 7-8), and 178 (59%) had DWI lesions. The incidence of DWI lesions was higher in patients with systolic blood pressure (SBP) reduction ≥ 80 mm Hg in first 24 h (76%). In adjusted models, factors associated with DWI lesions were as follows: admission intraventricular hematoma volume (p = 0.03), decrease in SBP ≥ 80 mm Hg from admission to day 1 (p = 0.03), and moderate-to-severe white matter disease (p = 0.01). Patients with DWI lesions had higher odds of severe disability at 1 month (p = 0.04), 6 months (p = 0.036), and 12 months (p < 0.01). No evidence of effect modification by cerebral small vessel disease on blood pressure was found. CONCLUSIONS: In patients with large hypertensive ICH, white matter disease, intraventricular hemorrhage volume, and large reductions in SBP over the first 24 h were independently associated with DWI lesions. Further investigation of potential hemodynamic mechanisms of ischemic injury after large ICH is warranted.

Cerebral small vessel disease modifies outcomes after minimally invasive surgery for intracerebral haemorrhage.

BACKGROUND: Minimally invasive surgery (MIS) for spontaneous supratentorial intracerebral haemorrhage (ICH) is controversial but may be beneficial if end-of-treatment (EOT) haematoma volume is reduced to ≤15 mL. We explored whether MRI findings of cerebral small vessel disease (CSVD) modify the effect of MIS on long-term outcomes. METHODS: Prespecified blinded subgroup analysis of 288 subjects with qualified imaging sequences from the phase 3 Minimally Invasive Surgery Plus Alteplase for Intracerebral Haemorrhage Evacuation (MISTIE) trial. We tested for heterogeneity in the effects of MIS and MIS+EOT volume ≤15 mL on the trial's primary outcome of good versus poor function at 1 year by the presence of single CSVD features and CSVD scores using multivariable models. RESULTS: Of 499 patients enrolled in MISTIE III, 288 patients had MRI, 149 (51.7%) randomised to MIS and 139 (48.3%) to standard medical care (SMC). Median (IQR) ICH volume was 42 (30-53) mL. In the full MRI cohort, there was no statistically significant heterogeneity in the effects of MIS versus SMC on 1-year outcomes by any specific CSVD feature or by CSVD scores (all Pinteraction >0.05). In 94 MIS patients with EOT ICH volume ≤15 mL, significant reduction in odds of poor outcome was found with cerebral amyloid angiopathy score <2 (OR, 0.14 (0.05-0.42); Pinteraction=0.006), absence of lacunes (OR, 0.37 (0.18-0.80); Pinteraction=0.02) and absence of severe white matter hyperintensities (WMHs) (OR, 0.22 (0.08-0.58); Pinteraction=0.03). CONCLUSIONS: Following successful haematoma reduction by MIS, we found significantly lower odds of poor functional outcome with lower total burden of CSVD in addition to absence of lacunes and severe WMHs. CSVD features may have utility for prognostication and patient selection in clinical trials of MIS.

The third Intensive Care Bundle with Blood Pressure Reduction in Acute Cerebral Haemorrhage Trial (INTERACT3): an international, stepped wedge cluster randomised controlled trial.

BACKGROUND: Early control of elevated blood pressure is the most promising treatment for acute intracerebral haemorrhage. We aimed to establish whether implementing a goal-directed care bundle incorporating protocols for early intensive blood pressure lowering and management algorithms for hyperglycaemia, pyrexia, and abnormal anticoagulation, implemented in a hospital setting, could improve outcomes for patients with acute spontaneous intracerebral haemorrhage. METHODS: We performed a pragmatic, international, multicentre, blinded endpoint, stepped wedge cluster randomised controlled trial at hospitals in nine low-income and middle-income countries (Brazil, China, India, Mexico, Nigeria, Pakistan, Peru, Sri Lanka, and Viet Nam) and one high-income country (Chile). Hospitals were eligible if they had no or inconsistent relevant, disease-specific protocols, and were willing to implement the care bundle to consecutive patients (aged ≥18 years) with imaging-confirmed spontaneous intracerebral haemorrhage presenting within 6 h of the onset of symptoms, had a local champion, and could provide the required study data. Hospitals were centrally randomly allocated using permuted blocks to three sequences of implementation, stratified by country and the projected number of patients to be recruited over the 12 months of the study period. These sequences had four periods that dictated the order in which the hospitals were to switch from the control usual care procedure to the intervention implementation of the care bundle procedure to different clusters of patients in a stepped manner. To avoid contamination, details of the intervention, sequence, and allocation periods were concealed from sites until they had completed the usual care control periods. The care bundle protocol included the early intensive lowering of systolic blood pressure (target <140 mm Hg), strict glucose control (target 6·1-7·8 mmol/L in those without diabetes and 7·8-10·0 mmol/L in those with diabetes), antipyrexia treatment (target body temperature ≤37·5°C), and rapid reversal of warfarin-related anticoagulation (target international normalised ratio <1·5) within 1 h of treatment, in patients where these variables were abnormal. Analyses were performed according to a modified intention-to-treat population with available outcome data (ie, excluding sites that withdrew during the study). The primary outcome was functional recovery, measured with the modified Rankin scale (mRS; range 0 [no symptoms] to 6 [death]) at 6 months by masked research staff, analysed using proportional ordinal logistic regression to assess the distribution in scores on the mRS, with adjustments for cluster (hospital site), group assignment of cluster per period, and time (6-month periods from Dec 12, 2017). This trial is registered at Clinicaltrials.gov (NCT03209258) and the Chinese Clinical Trial Registry (ChiCTR-IOC-17011787) and is completed. FINDINGS: Between May 27, 2017, and July 8, 2021, 206 hospitals were assessed for eligibility, of which 144 hospitals in ten countries agreed to join and were randomly assigned in the trial, but 22 hospitals withdrew before starting to enrol patients and another hospital was withdrawn and their data on enrolled patients was deleted because regulatory approval was not obtained. Between Dec 12, 2017, and Dec 31, 2021, 10 857 patients were screened but 3821 were excluded. Overall, the modified intention-to-treat population included 7036 patients enrolled at 121 hospitals, with 3221 assigned to the care bundle group and 3815 to the usual care group, with primary outcome data available in 2892 patients in the care bundle group and 3363 patients in the usual care group. The likelihood of a poor functional outcome was lower in the care bundle group (common odds ratio 0·86; 95% CI 0·76-0·97; p=0·015). The favourable shift in mRS scores in the care bundle group was generally consistent across a range of sensitivity analyses that included additional adjustments for country and patient variables (0·84; 0·73-0·97; p=0·017), and with different approaches to the use of multiple imputations for missing data. Patients in the care bundle group had fewer serious adverse events than those in the usual care group (16·0% vs 20·1%; p=0·0098). INTERPRETATION: Implementation of a care bundle protocol for intensive blood pressure lowering and other management algorithms for physiological control within several hours of the onset of symptoms resulted in improved functional outcome for patients with acute intracerebral haemorrhage. Hospitals should incorporate this approach into clinical practice as part of active management for this serious condition. FUNDING: Joint Global Health Trials scheme from the Department of Health and Social Care, the Foreign, Commonwealth & Development Office, and the Medical Research Council and Wellcome Trust; West China Hospital; the National Health and Medical Research Council of Australia; Sichuan Credit Pharmaceutic and Takeda China.

Increasing burden of stroke in China: A systematic review and meta-analysis of prevalence, incidence, mortality, and case fatality.

BACKGROUND: The epidemiology of stroke is evolving in China as the population undergoes demographic, lifestyle, and economic transitions. An updated review is pertinent to providing feedback on current, and in planning future, prevention and management strategies. AIMS: To identify high-quality epidemiological studies for quantifying the prevalence, incidence, mortality, and case fatality for stroke in China. METHODS: A search was undertaken across a range of bibliographic databases on 30 November 2021 without time limitation. Assessments were made of the risk of bias of the included studies. The outcomes were synthesized using a random-effects model. Subgroup analysis and meta-regression models were used to define the source of heterogeneity. RESULTS: Of 9407 identified records, 26 population-based studies were included. Due to significant heterogeneity across the studies, the original range for crude rates of indices was wide. The pooled annual prevalence was 1329.5/100,000 (95% confidence interval (CI) 713.6-2131.9, p < 0.001), incidence 442.1/100,000 (327.6-573.8, p < 0.001), mortality 154.1/100,000 (52.6-308.8, I2 = 100%, p < 0.001), and case fatality 35.8% (26.1% to 46.1%, I2 = 97%, p < 0.001). The prevalence and incidence of stroke have increased, but stroke-related case fatality has declined in China over recent decades. There are significant regional and rural-urban differences in incidence rates. CONCLUSION: Despite improved public health policies and healthcare delivery, the burden of stroke remains high in China. Further coordinated efforts are required in prevention and community care to offset the likelihood of further expansion in the absolute number of stroke cases in this large population.

The second randomized controlled ENhanced Control of Hypertension ANd Thrombectomy strokE stuDy (ENCHANTED2): Protocol and progress.

BACKGROUND: Uncertainty exists over the optimal level of blood pressure (BP) after mechanical thrombectomy (MT) for acute ischemic stroke (AIS). OBJECTIVES: We aim to determine the effectiveness and safety of intensive BP-lowering following MT reperfusion of large-vessel occlusion (LVO)-related AIS. DESIGN: The second ENhanced Control of Hypertension ANd Thrombolysis strokE stuDy (ENCHANTED2) is an investigator-initiated, multicenter, prospective, randomized, open, blinded-endpoint (PROBE) trial of intensive systolic BP (SBP) control in reperfused (extended treatment in cerebral infarction (eTICI) classification 2b/2c/3) LVO-AIS patients with persistent hypertension (SBP ⩾ 140 mmHg) at 60+ sites in China, and Australia and the United Kingdom. Eligible patients are centrally randomly allocated to more- (target SBP ⩽ 120 mmHg within 1 h) or less-intensive (target SBP 140-180 mmHg) BP management, to be maintained for 72 h. Primary outcome is an ordinal shift analysis of scores on the modified Rankin scale (mRS) at 90 days. Sample size of 2257 patients provides 90% power to detect a 6.5% absolute reduction in poor outcome from more-intensive BP-lowering using ordinal logistic regression. PROGRESS: Recruitment started in China in July 2020. At a meeting of the independent Data and Safety Monitoring Board in March 2022 to review primary outcome data available for 347 patients, they recommended suspension of recruitment due to safety concerns in the more-intensive group; which was implemented by the Trial Steering Committee (TSC) with 817 randomized patients only in China. The TSC then stopped recruitment after the safety concerns persisted on further review of the data in June 2022. The TSC will make a decision on restarting the trial with modification of the protocol when the results are made public. DISCUSSION: ENCHANTED2 will provide further randomized evidence on the role of intensive BP-lowering after reperfusion in MT-treated AIS patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT04140110; registered 25 October 2019.

Intensive blood pressure control after endovascular thrombectomy for acute ischaemic stroke (ENCHANTED2/MT): a multicentre, open-label, blinded-endpoint, randomised controlled trial.

BACKGROUND: The optimum systolic blood pressure after endovascular thrombectomy for acute ischaemic stroke is uncertain. We aimed to compare the safety and efficacy of blood pressure lowering treatment according to more intensive versus less intensive treatment targets in patients with elevated blood pressure after reperfusion with endovascular treatment. METHODS: We conducted an open-label, blinded-endpoint, randomised controlled trial at 44 tertiary-level hospitals in China. Eligible patients (aged ≥18 years) had persistently elevated systolic blood pressure (≥140 mm Hg for >10 min) following successful reperfusion with endovascular thrombectomy for acute ischaemic stroke from any intracranial large-vessel occlusion. Patients were randomly assigned (1:1, by a central, web-based program with a minimisation algorithm) to more intensive treatment (systolic blood pressure target <120 mm Hg) or less intensive treatment (target 140-180 mm Hg) to be achieved within 1 h and sustained for 72 h. The primary efficacy outcome was functional recovery, assessed according to the distribution in scores on the modified Rankin scale (range 0 [no symptoms] to 6 [death]) at 90 days. Analyses were done according to the modified intention-to-treat principle. Efficacy analyses were performed with proportional odds logistic regression with adjustment for treatment allocation as a fixed effect, site as a random effect, and baseline prognostic factors, and included all randomly assigned patients who provided consent and had available data for the primary outcome. The safety analysis included all randomly assigned patients. The treatment effects were expressed as odds ratios (ORs). This trial is registered at ClinicalTrials.gov, NCT04140110, and the Chinese Clinical Trial Registry, 1900027785; recruitment has stopped at all participating centres. FINDINGS: Between July 20, 2020, and March 7, 2022, 821 patients were randomly assigned. The trial was stopped after review of the outcome data on June 22, 2022, due to persistent efficacy and safety concerns. 407 participants were assigned to the more intensive treatment group and 409 to the less intensive treatment group, of whom 404 patients in the more intensive treatment group and 406 patients in the less intensive treatment group had primary outcome data available. The likelihood of poor functional outcome was greater in the more intensive treatment group than the less intensive treatment group (common OR 1·37 [95% CI 1·07-1·76]). Compared with the less intensive treatment group, the more intensive treatment group had more early neurological deterioration (common OR 1·53 [95% 1·18-1·97]) and major disability at 90 days (OR 2·07 [95% CI 1·47-2·93]) but there were no significant differences in symptomatic intracerebral haemorrhage. There were no significant differences in serious adverse events or mortality between groups. INTERPRETATION: Intensive control of systolic blood pressure to lower than 120 mm Hg should be avoided to prevent compromising the functional recovery of patients who have received endovascular thrombectomy for acute ischaemic stroke due to intracranial large-vessel occlusion. FUNDING: The Shanghai Hospital Development Center; National Health and Medical Research Council of Australia; Medical Research Futures Fund of Australia; China Stroke Prevention; Shanghai Changhai Hospital, Science and Technology Commission of Shanghai Municipality; Takeda China; Hasten Biopharmaceutic; Genesis Medtech; Penumbra.

One-Year Outcome Trajectories and Factors Associated with Functional Recovery Among Survivors of Intracerebral and Intraventricular Hemorrhage With Initial Severe Disability.

Importance: Patients who survive severe intracerebral hemorrhage (ICH) and intraventricular hemorrhage (IVH) typically have poor functional outcome in the short term and understanding of future recovery is limited. Objective: To describe 1-year recovery trajectories among ICH and IVH survivors with initial severe disability and assess the association of hospital events with long-term recovery. Design, Setting, and Participants: This post hoc analysis pooled all individual patient data from the Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Hemorrhage phase 3 trial (CLEAR-III) and the Minimally Invasive Surgery Plus Alteplase for Intracerebral Hemorrhage Evacuation (MISTIE-III) phase 3 trial in multiple centers across the US, Canada, Europe, and Asia. Patients were enrolled from August 1, 2010, to September 30, 2018, with a follow-up duration of 1 year. Of 999 enrolled patients, 724 survived with a day 30 modified Rankin Scale score (mRS) of 4 to 5 after excluding 13 participants with missing day 30 mRS. An additional 9 patients were excluded because of missing 1-year mRS. The final pooled cohort included 715 patients (71.6%) with day 30 mRS 4 to 5. Data were analyzed from July 2019 to January 2022. Exposures: CLEAR-III participants randomized to intraventricular alteplase vs placebo. MISTIE-III participants randomized to stereotactic thrombolysis of hematoma vs standard medical care. Main Outcomes and Measures: Primary outcome was 1-year mRS. Patients were dichotomized into good outcome at 1 year (mRS 0 to 3) vs poor outcome at 1 year (mRS 4 to 6). Multivariable logistic regression models assessed associations between prospectively adjudicated hospital events and 1-year good outcome after adjusting for demographic characteristics, ICH and IVH severity, and trial cohort. Results: Of 715 survivors, 417 (58%) were male, and the overall mean (SD) age was 60.3 (11.7) years. Overall, 174 participants (24.3%) were Black, 491 (68.6%) were White, and 49 (6.9%) were of other races (including Asian, Native American, and Pacific Islander, consolidated owing to small numbers); 98 (13.7%) were of Hispanic ethnicity. By 1 year, 129 participants (18%) had died and 308 (43%) had achieved mRS 0 to 3. In adjusted models for the combined cohort, diabetes (adjusted odds ratio [aOR], 0.50; 95% CI, 0.26-0.96), National Institutes of Health Stroke Scale (aOR, 0.93; 95% CI, 0.90-0.96), severe leukoaraiosis (aOR, 0.30; 95% CI, 0.16-0.54), pineal gland shift (aOR, 0.87; 95% CI, 0.76-0.99]), acute ischemic stroke (aOR, 0.44; 95% CI, 0.21-0.94), gastrostomy (aOR, 0.30; 95% CI, 0.17-0.50), and persistent hydrocephalus by day 30 (aOR, 0.37; 95% CI, 0.14-0.98) were associated with lack of recovery. Resolution of ICH (aOR, 1.82; 95% CI, 1.08-3.04) and IVH (aOR, 2.19; 95% CI, 1.02-4.68) by day 30 were associated with recovery to good outcome. In the CLEAR-III model, cerebral perfusion pressure less than 60 mm Hg (aOR, 0.30; 95% CI, 0.13-0.71), sepsis (aOR, 0.05; 95% CI, 0.00-0.80), and prolonged mechanical ventilation (aOR, 0.96; 95% CI, 0.92-1.00 per day), and in MISTIE-III, need for intracranial pressure monitoring (aOR, 0.35; 95% CI, 0.12-0.98), were additional factors associated with poor outcome. Thirty-day event-based models strongly predicted 1-year outcome (area under the receiver operating characteristic curve [AUC], 0.87; 95% CI, 0.83-0.90), with significantly improved discrimination over models using baseline severity factors alone (AUC, 0.76; 95% CI, 0.71-0.80; P < .001). Conclusions and Relevance: Among survivors of severe ICH and IVH with initial poor functional outcome, more than 40% recovered to good outcome by 1 year. Hospital events were strongly associated with long-term functional recovery and may be potential targets for intervention. Avoiding early pessimistic prognostication and delaying prognostication until after treatment may improve ability to predict future recovery.

Tryptophan and the innate intestinal immunity: Crosstalk between metabolites, host innate immune cells, and microbiota.

The intestinal mucosal barrier is critical for the absorption of nutrients and the health of both humans and animals. Recent publications from clinical and experimental studies have shown the importance of the nutrients-bacteria-host interaction for the intestinal homeostasis. Dysfunction of these interactions has been reported to be associated with metabolic disorders and development of intestinal diseases such as the irritable bowel syndrome and inflammatory bowel diseases. Tryptophan and its metabolites, including kynurenine, kynurenic acid, and 5-hydroxytrptamine, can influence the proliferation of enterocytes, intestinal integrity, and immune response, as well as intestinal microbiota, therefore, regulating and contributing to the intestinal health. In this review, we highlight recent findings on the effect of tryptophan and its metabolites on the mucosal barrier and intestinal homeostasis and its regulation of innate immune response. Moreover, we present the signaling pathways related to Trp metabolism, such as mammalian target of rapamycin, aryl hydrocarbon receptor, and pregnane X receptor, which contribute to the intestinal homeostasis and discuss future perspectives on spontaneous interference in host tryptophan metabolism as potential clinical strategies of intestinal diseases.

Cerebral Microbleeds and Acute Hematoma Characteristics in the ATACH-2 and MISTIE III Trials.

BACKGROUND AND OBJECTIVES: To study the relationship between the presence of cerebral microbleeds (CMBs) and acute hematoma characteristics among patients with primary intracerebral hemorrhage (ICH). METHODS: We pooled individual patient data from the Antihypertensive Treatment of Acute Cerebral Hemorrhage 2 (ATACH-2) trial and the Minimally Invasive Surgery Plus Alteplase for Intracerebral Hemorrhage Evacuation phase 3 (MISTIE III) trial. We included individuals with a brain MRI scan. Exposure was the presence of a CMB. The coprimary outcomes were admission ICH volume and hematoma expansion. Mixed-effects linear and logistic regression models were used, with demographics and comorbid conditions considered fixed effects and the study cohort treated as a random effect. Additional analyses assessed the relationship between CMB topography and number and hematoma characteristics. RESULTS: Of the 1,499 patients with ICH enrolled in the parent trials, 466 (31.1%) were included in this analysis, and 231 (49.6%) patients had CMBs. In adjusted models, presence of CMBs was associated with smaller ICH volume (ß = -0.26, 95% confidence interval [CI] -0.44 to -0.08) and lower odds of hematoma expansion (odds ratio 0.65, 95% CI 0.40-0.95; p = 0.04). The strength of association between CMBs and hematoma characteristics increased with increasing number of CMBs. The location of the CMBs and the severity of leukoaraiosis did not modify these results. DISCUSSION: In a pooled cohort of patients with ICH, our results are consistent with the hypothesis that more severe underlying small vessel disease, as represented by CMBs, leads to smaller baseline hematoma volumes and reduced hematoma expansion. Underlying cerebral small vessel disease may be of prognostic significance after ICH. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov Identifier: NCT01176565 and NCT01827046. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that the presence of microbleeds on MRI is associated with a smaller ICH volume at presentation and a lower rate of hematoma expansion on follow-up imaging.

Intracranial Pressure and Cerebral Perfusion Pressure in Large Spontaneous Intracranial Hemorrhage and Impact of Minimally Invasive Surgery.

Introduction: We investigated the effect of hematoma volume reduction with minimally invasive surgery (MIS) on intracranial pressure (ICP) and cerebral perfusion pressure (CPP) in patients with large spontaneous intracerebral hemorrhage (ICH). Methods: Post-hoc analysis of the Minimally Invasive Surgery Plus Alteplase for Intracerebral Hemorrhage Evacuation (MISTIE III) study, a clinical trial with blinded outcome assessments. The primary outcome was the proportion of ICP readings ≥20 and 30 mmHg, and CPP readings <70 and 60 mm Hg. Secondary outcomes included major disability (modified Rankin scale >3) and mortality at 30 and 365 days. We assessed the relationship between proportion of high ICP and low CPP events and MIS using binomial generalized linear models, and outcomes using multiple logistic regression. Results: Of 499 patients enrolled in MISTIE III, 72 patients had guideline based ICP monitors placed, 34 in the MIS group and 38 in control (no surgery) group. Threshold ICP and CPP events ≥20/ <70 mmHg occurred in 31 (43.1%) and 52 (72.2%) patients respectively. On adjusted analyses, proportion of ICP readings ≥20 and 30 mmHg were significantly lower in the MIS group vs. control group [Odds Ratio (OR) 0.27, 95% Confidence Interval [CI] 0.11-0.63 (p = 0.002); OR = 0.18, 0.04-0.75, p = 0.02], respectively. Proportion of CPP readings <70 and 60 mm Hg were also significantly lower in MIS patients [OR 0.31, 95% CI 0.15-0.63 (p = 0.001); OR 0.30, 95% CI 0.11-0.83 (p = 0.02)], respectively. Higher proportions of CPP readings <70 and 60 mm were significantly associated with short term mortality (p = 0.04), and (p = 0.006), respectively. Long term mortality was significantly associated with higher proportion of time with ICP ≥ 20 (p = 0.04), ICP ≥ 30 (p = 0.04), and CPP <70 mmHg (p = 0.01). Conclusion: Our results are consistent with the hypothesis that surgical reduction of ICH volume decreases proportion of high ICP and low CPP events and that these variables are associated with short- and long-term mortality.

The Prognostic Value of the Acute Phase Systemic Immune-Inflammation Index in Patients With Intracerebral Hemorrhage.

Background and Purpose: The systemic immune-inflammation index (SII) is a novel prognostic index in various diseases. We evaluated the predictive value of SII in patients with intracerebral hemorrhage (ICH). Methods: Patients with primary spontaneous ICH were enrolled. SII was constructed based on peripheral platelet (P), neutrophil (N), and lymphocyte (L) and defined as P*N/L. In addition to admission testing, acute phase SII was collected to analyze the potential dynamic change. Poor outcome was defined as modified Rankin Scale of more than 3 at 90 days. Results: We included 291 patients; 98 (34%) achieved favorable functional outcomes. Day-1 SII was higher and was more related to poor outcome than was admission SII. Median time of day-1 SII was 29 h from onset. Day-1 SII had an OR in outcome (mRS >3) 1.74 (95% CI = 1.03-3.00, p = 0.04). The binary cutoff point of SII calculated using the area under the curve (AUC) method was 1,700 × 109/L, AUC 0.699 (95% CI = 0.627-0.774) (sensitivity 53.3%, specificity 77.3%) (OR = 2.36, 95% CI = 1.09-5.26, p = 0.03). Conclusions: SII, especially day-1 SII, was highly associated with 90-day functional outcome in patients with ICH and could be used to predict outcomes.

Changes in Characteristics, Treatment and Outcome in Patients with Hemorrhagic Stroke During COVID-19.

BACKGROUND AND PURPOSE: The coronavirus disease 2019 (COVID-19) pandemic has had a comprehensive impact on healthcare services worldwide. We sought to determine whether COVID-19 affected the treatment and prognosis of hemorrhagic stroke in a regional medical center in mainland China. METHODS: Patients with hemorrhagic stroke admitted in the Neurosurgery Department of West China Hospital from January 24, 2020, to March 25, 2020 (COVID-19 period), and from January 24, 2019, to March 25, 2019 (pre-COVID-19 period), were identified. Clinical characteristics, hospital arrival to neurosurgery department arrival time (door-to-department time), reporting rate of pneumonia and 3-month mRS (outcome) were compared. RESULTS: A total of 224 patients in the pre-COVID-19 period were compared with 126 patients in the COVID-19 period. Milder stroke severity was observed in the COVID-19 period (NIHSS 6 [2-20] vs. 3 [2-15], p = 0.005). The median door-to-department time in the COVID-19 period was approximately 50 minutes longer than that in the pre-COVID-19 period (96.5 [70.3-193.3] vs. 144.5 [93.8-504.5], p = 0.000). A higher rate of pneumonia complications was reported in the COVID-19 period (40.6% vs. 60.7%, p = 0.000). In patients with moderate hemorrhagic stroke, the percentage of good outcomes (mRS < 3) in the pre-COVID-19 period was much higher than that in the COVID-19 period (53.1% vs. 26.3%, p = 0.047). CONCLUSIONS: COVID-19 may have several impacts on the treatment of hemorrhagic stroke and may influence the clinical outcomes of specific patients. Improvements in the treatment process for patients with moderate stroke may help to improve the overall outcome of hemorrhagic stroke during COVID-19.

Geographic Variations of Stroke Incidence in Chinese Communities: An 18-Year Prospective Cohort Study from 1997 to 2015.

BACKGROUND AND PURPOSE: As a leading cause of disability and death in China, stroke as well as its epidemiologic features have gained increasing attention. Prior studies, however, have overgeneralized the north-to-south gradient in China. Whether the differences exist across urban and rural areas remains unexplored. This study therefore aims to investigate the north-to-south gradient in stroke incidence across urban and rural China. METHODS: The present prospective cohort study analyzed data from the China Health and Nutrition Survey 1997 to 2015. By including 16,917 individuals from diverse social contexts, we calculated the age-standardized incidence of stroke across regions and the age-adjusted risk ratio (aRR). Cox proportional hazards models with time-varying covariates were employed to analyze variations in incident stroke. RESULTS: During the follow-up, age-standardized incidence of stroke ranged from 4.17 per 1,000 person-years (95% confidence interval [CI], 3.38 to 4.96) in the north region to 1.95 (95% CI, 1.60 to 2.30) in the south region (aRR, 2.04; 95% CI, 1.58 to 2.64; P<0.001). The north-to-south gradient of stroke incidence was observed only in rural areas, but not in urban areas. Hierarchical modelling analyses further indicated that the regional differences could be mostly explained by the disparities in the prevalence of hypertension. CONCLUSIONS: The present study extends the current evidence on the north-to-south gradient by demonstrating that the difference varied across urban and rural China. Our findings highlight the importance of hypertension management as the measure for alleviating regional differences in stroke incidence.

A Pooled Analysis of Diffusion-Weighted Imaging Lesions in Patients With Acute Intracerebral Hemorrhage.

Importance: The etiology and significance of diffusion-weighted imaging (DWI) lesions in patients with acute intracerebral hemorrhage (ICH) remain unclear. Objective: To evaluate which factors are associated with DWI lesions, whether associated factors differ by ICH location, and whether DWI lesions are associated with functional outcomes. Design, Setting, and Participants: This analysis pooled individual patient data from 3 randomized clinical trials (Minimally Invasive Surgery Plus Alteplase for Intracerebral Hemorrhage Evacuation phase 3 trial, Antihypertensive Treatment of Acute Cerebral Hemorrhage trial, and Intracerebral Hemorrhage Deferoxamine phase 2 trial) and 1 multicenter prospective study (Ethnic/Racial Variations of Intracerebral Hemorrhage). Patients were enrolled from August 1, 2010, to September 30, 2018. Of the 4782 patients, 1788 who underwent magnetic resonance imaging scans of the brain were included. Data were analyzed from July 1 to December 31, 2019. Main Outcomes and Measures: The primary outcome consisted of factors associated with DWI lesions. Secondary outcomes were poor functional outcome, defined as a modified Rankin score (mRS) of 4 to 6, and mortality, both assessed at 3 months. Mixed-effects logistic regression was used to evaluate the association between exposures and outcomes. Subgroup analyses stratified by hematoma location were performed. Results: After exclusion of 36 patients with missing data on DWI lesions, 1752 patients were included in the analysis (1019 men [58.2%]; mean [SD] age, 60.8 [13.3] years). Diffusion-weighted imaging lesions occurred in 549 patients (31.3%). In mixed-effects regression models, factors associated with DWI lesions included younger age (odds ratio [OR] per year, 0.98; 95% CI, 0.97-0.99), black race (OR, 1.64; 95% CI, 1.17-2.30), admission systolic blood pressure (OR per 10-mm Hg increase, 1.13; 95% CI, 1.08-1.18), baseline hematoma volume (OR per 10-mL increase, 1.12; 95% CI, 1.02-1.22), cerebral microbleeds (OR, 1.85; 95% CI, 1.39-2.46), and leukoaraiosis (OR, 1.59; 95% CI, 1.67-2.17). Diffusion-weighted imaging lesions were independently associated with poor mRS (OR, 1.50; 95% CI, 1.13-2.00), but not with mortality (OR, 1.11; 95% CI, 0.72-1.71). In subgroup analyses, similar factors were associated with DWI lesions in lobar and deep ICH. Diffusion-weighted imaging lesions were associated with poor mRS in deep but not lobar ICH. Conclusions and Relevance: In a large, heterogeneous cohort of prospectively identified patients with ICH, results were consistent with the hypothesis that DWI lesions represent acute sequelae of chronic cerebral small vessel disease, particularly hypertensive vasculopathy. Diffusion-weighted imaging lesions portend a worse prognosis after ICH, mainly deep hemorrhages.

Manipulating the transmission of vector beam with spatially polarized atomic ensemble.

Vector beams (VBs) with potential applications are successfully utilized in many fields as light sources with a spatially-varying polarization profile in recent years. Here, we study the transmission of a VB by manipulating atomic polarization via the optical pumping effect. By using hybridly and radially polarized beams as pump and probe beams in a counter-propagating configuration, we observe a four-petal pattern intensity distribution of probe beam, and the four-petal pattern rotates with the polarization state orientation of the pump beam. The results show a polarization dependent absorption in the atomic media. We experimentally demonstrate the absorption characteristics under different polarization combinations of pump and probe beams. The Jones matrix method is used to explain this phenomenon and the simulations are consistent with the experimental observation. Our results may provide a sound foundation for applications in optical manipulation and quantum information in atomic ensembles.